Bombesin (BN) and BN-like peptides (BN-LPs) are novel gut-brain peptides. In mammals, they regulate digestive functions, evoke stereotyped behaviors, are important in thermoregulation, are putative growth factors in small cell lung carcinoma, and may play a role in synaptogenesis. Despite efforts to develop selective BN receptor antagonists, only substance P (SP) antagonists activity. Little is known of their degradation in brain. BN may be a potent neurotransmitter or neuromodulator. Recent evidence suggests it regulates serotonin (5-HT) release. Despite their great potency and spectrum of activity, little is known of their neurochemistry and how this relates to behavioral activity. The overall aim of this proposal is to investigate the basic neurochemistry of BN and BN-like peptides in the hypothalamus, which has high levels of BN- LPs and receptors, and to determine if there is an association with the thermoregulatory effects of BN. Effects of BN-LPs on 5-HT, norepinephrine (NE) and dopamine (DA) release, and calcium uptake will be explored. The relevance of these effects will be assessed by examining BN-induced hypothermia and the 5-HT motor syndrome in both naive and BN tolerant rats. Methods to be employed include stimulation-induced release of labeled neurotransmitter from superfused brain slices, and uptake of labeled neurotransmitter and calcium-45 into synaptosomes. Relative potencies of the N-LPs on these processes will be determined. The effects of BN-LPs on the levels of metabolites of 5-HT, NE and DA will be assessed using high performance liquid chromatography with electrochemical detection. Use of specific BN fragments, SP antagonists, and peptidase inhibitors will help focus on receptor specificity and degradation. The pattern of neurochemical changes will be related to existing models of thermoregulation and to their dose-response characteristics and relative potencies in the uptake, release and metabolite studies, and will provide a focus for further studies. This research will provide a broader understanding of the neurochemistry of these peptides which will serve to elucidate the mechanism by which they affect behavior and other physiological functions.